The small molecule BI-2852 induces a nonfunctional dimer of KRAS
Timothy H. Tran, Patrick Alexander, Srisathiyanarayanan Dharmaiah, Constance Agamasu, Dwight V. Nissley, Frank McCormick, Dominic Esposito, Dhirendra K. Simanshu, Andrew G. Stephen, Trent E. Balius
Abstract
In Kessler et al. (1), the small molecule BI-2852 is shown to bind—at nanomolar affinity—to KRAS between switch I and II, inhibiting interactions with effectors. Here, we identify an alternative explanation for the inhibitory activity. While investigating the BI-2852 KRAS complex (Protein Data Bank [PDB] code 6GJ8), we noticed, by revealing the molecules in the neighboring unit cell, BI-2852 induces a KRAS dimer with rotational symmetry. This dimer complex consists of four molecules (two of BI-2852 and two of KRAS; Fig. 1 A ). Fig. 1. Dimer of KRAS with BI-2852. ( A ) Cartoon of BI-2852 KRAS dimer. Lig1 (cyan) and Lig2 (magenta) interact with both Ras1 (beige) and Ras2 (orange). ( B ) KRAS (ribbons) and key side chains are shown. ( C ) Zoom-in of the binding site: salt–bridge interactions shown (dashed lines). ( D ) Lid (green) and Basin (purple) are indicated on Ras1. Both Lig1 and Lig2 are shown on Ras1. The indole rings, colored green and purple, engage the Lid and Basin, respectively. ( E ) Absorbance A 280 plotted as a function of elution volume: … [↵][1]1To whom correspondence may be addressed. Email: trent.balius{at}nih.gov. [1]: #xref-corresp-1-1